The hepatitis C virus (HCV) is the leading cause of chronic liver disease worldwide (Boyer, N. et al. J Hepatol. 32:98-112, 2000). An estimated 170 million persons are infected with HCV worldwide. (Boyer, N. et al, J Hepatol. 32:98-112, 2000). A significant focus of current antiviral research is directed toward the development of improved methods of treatment of chronic HCV infections in humans (Di Besceglie, A. M. and Bacon, B. R., Scientific American, October: 80-85, (1999)). A number of HCV treatments are reviewed by Bymock et al. in Antiviral Chemistry & Chemotherapy, 11:2; 79-95 (2000).
Viral serine protease and the RNA-dependent RNA polymerase (RdRp) are the best studied targets for the development of novel HCV therapeutic agents. The NS5B polymerase is a target for inhibitors in early human clinical trials (Sommadossi, J., WO 01/90121 A2). These enzymes have been extensively characterized at the biochemical and structural level, with screening assays for identifying selective inhibitors (De Clercq, E. (2001) J. Pharmacol. Exp. Ther. 297:1-10; De Clercq, E. (2001) J. Clin. Virol. 22:73-89). Recent structural work on HCV RdRp has identified catalytic and regulatory nucleotide binding sites (Bressanelli S. et al (2002) J. Virol. 76:3482-92). Since HCV does not replicate in the laboratory, there are difficulties in developing cell-based assays and preclinical animal systems.
Currently, there are two primary antiviral compounds, ribavirin and interferon-alpha (α) (IFN) which are used for the treatment of chronic HCV infections in humans. Ribavirin alone is not effective in reducing viral RNA levels, has significant toxicity, and is known to induce anemia. The combination of IFN and ribavirin for the treatment of HCV infection has been reported to be effective in the treatment of IFN-naive patients (Battaglia, A. M. et al., Ann. Pharmacother. 34:487-494, 2000). Results are promising for this combination treatment both before hepatitis develops or when histological disease is present (Berenguer, M. et al. (1998) Antivir. Ther. 3 (Suppl. 3):125-136), but there is a need for improved anti-HCV therapeutic agents, i.e. drugs having improved antiviral and pharmacokinetic properties with enhanced activity against development of HCV resistance, improved oral bioavailability, greater efficacy, fewer undesirable side effects and extended effective half-life in vivo (De Francesco, R. et al (2003) Antiviral Research 58:1-16). The instant invention provides improved anti-HCV therapeutic agents.
Unsaturated linker phosphonate analogs of nucleotides have been disclosed in U.S. Pat. No. 5,672,697; WO 9607666; EP 629633; US 2006074035; J. Med. Chem. 2005, 48, 2867-2875; Biochemistry 2002, 41, 7725-7731; Org. Lett. 2001, 3, 3365-3367; Org. Lett. 2001, 3, 2756-2768; Tetrahedron. Lett. 2000, 41, 4513-4517; Bioorg. & Med. Chem. 2000, 8, 2501-2509; J. Chem. Soc., Perkins Trans. 1999, 2585-2590; Synlett 1999, 1124-1126; Biochemistry 1998, 37, 9043-9051; Tetrahedron Lett. 1996, 37, 6239-6242; Tetrahedron 1995, 51, 4145-4160; Nucleic Acids Research 1995, 23, 893-900; Nucleosides Nucleotides 1995, 14, 871-874; Antiviral Chemistry Chemotherapy 1994, 5, 221-228; Tetrahedron Lett. 1993, 34, 2723-2726; EP 479640; J. Med. Chem. 1992, 35, 3192-3196; Nucleosides & Nucleotides 1992, 11, 947-956; Acta Chemica Scandinavica 1991, 45, 766-767; Bioorganic Chemistry 1985, 13, 289-295; J. Med. Chem. 1982, 25, 806-812; J. Med. Chem. 1979, 22, 109-111; and Bioorganic Chemistry 1976, 5, 31-35. Unsaturated linker phosphonate derivatives of purine and pyrimidine compounds have been reported to be useful as antiviral agents (US 2003/0004345A1; EP 0532423A1; EP 0618214A1; EP 0701562B1; U.S. Pat. Nos. 5,817,647; 5,922,696; WO 94/22882).